1. Technical Field
This invention relates to a process for preparing a crystalline form of halobetasol propionate. The crystalline form of halobetasol propionate is characterized by an x-ray powder diffraction pattern having peaks at 10.0, 11.6, 12.9, 13.4, 14.5, 16.4, 17.6, and 23.5±0.2 degrees 2θ.
2. Background Art
Halobetasol propionate ((6α,11β,16β)-21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)pregna-1,4-diene-3,20-dione; CAS #66852-54-8) is a high potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Halobetasol propionate has the following chemical structure:

U.S. Pat. No. 4,619,921 (the '921 patent), issued in 1986, discloses the synthesis of halobetasol propionate. The '921 patent further discloses recrystallization of halobetasol propionate using a solvent system containing a mixture of methylene chloride and ether. The '921 patent discloses the melting point of the obtained crystalline form of halobetasol propionate (i.e., 220-221° C.), but does not expressly disclose the x-ray diffraction pattern.
Since 1992, halobetasol propionate has been marketed and on sale under the tradename ULTRAVATE® (Bristol-Myers Squibb Co., Princeton, N.J.) as an ointment and a cream. Both ULTRAVATE® ointment and ULTRAVATE® cream contain 0.05% (w/w) halobetasol propionate as the active ingredient. Halobetasol propionate is soluble in organic solvents, but is insoluble in water. Thus, halobetasol propionate is completely dissolved in organic solvent-based ULTRAVATE® ointment, but remains as a suspended solid in water-based ULTRAVATE® cream. The literature contains no published characterization data regarding the specific crystalline form of halobetasol propionate used or contained in ULTRAVATE® ointment and cream.
U.S. Patent Application Nos. 2004/0138191 (the '191 application) and 2004/0138192 (the '192 application) disclose x-ray powder diffraction, infrared, and differential scanning calorimetry characterization data for a total of six (6) crystalline forms of halobetasol propionate (i.e., Forms I, II, III, IV, V and VI). According to the '191 and '192 applications, crystallization using methylene chloride/ether (the solvent system disclosed in the '921 patent) at a ratio of 5:1 results in crystalline Form I of halobetasol propionate.
The six (6) crystalline forms of halobetasol propionate disclosed in the '191 and '192 applications were prepared using eight (8) different solvent systems. Apparently, there is no predictable correlation between the nature of the solvent system used (e.g., polarity, functional groups, hydrogen bonding ability) and the crystalline form of halobetasol propionate obtained. For example, crystallization from isopropanol, methanol/water, and methanol (all alcoholic solvent systems) yields three (3) different crystalline forms of halobetasol propionate (i.e., Forms III, IV, and VI, respectively). In addition, while crystallization from methylene chloride provides Form III of halobetasol propionate, crystallization from methylene chloride/ether provides Form I of halobetasol propionate.
A disadvantage of the crystallization processes disclosed in the '191 and '192 applications is that five (5) of the eight (8) solvent systems contain methylene chloride, toluene, or methanol. Therefore, these five (5) solvent systems are toxic. In addition, only three (3) of the eight (8) solvent systems disclosed in the '191 and '192 applications provide Form III of halobetasol propionate. Preliminary studies from our laboratory indicate that Form III of halobetasol propionate matches the crystalline form of halobetasol propionate present in ULTRAVATE® cream.
There is a continuing need for a process for preparing a crystalline form of halobetasol propionate, such as the crystalline form present in the commercial ULTRAVATE® cream. There is a need for a process that provides a crystalline form of halobetasol propionate in high yield and substantially free of impurities, employs a non-toxic solvent system, and is suitable for commercial scale use.